Efficacy and Safety of Mifepristone in the Treatment of Male US Veterans With Posttraumatic Stress Disorder

Key Points Question Is there evidence of a signal for clinical efficacy for the glucocorticoid receptor antagonist mifepristone in the treatment of male veterans with posttraumatic stress disorder? Findings In this randomized clinical trial of short-term mifepristone treatment (600 mg per day for 7 days) in 80 male veterans with posttraumatic stress disorder (41 receiving mifepristone and 39 receiving placebo), the difference in the clinical response rate to mifepristone vs placebo at 4 and 12 weeks was less than the predefined clinical margin used to define efficacy. Meaning These results do not support an indication for a phase 3 trial of this regimen in this heterogeneous population.

sleep disturbance), or quality of life (Friedman et al., 2007). Antipsychotics, mood-stabilizers, sedatives, and 23 hypnotics are also widely used, alone and in combinations, despite limited efficacy data and some concerns 24 regarding safety (e.g., metabolic and neurologic side effects). The extensive use of polypharmacy, incorporating 25 off-label medications and medications that have not been shown to be effective, highlights the limitations in 26 the current psychopharmacological approach to PTSD. There is clearly a need to develop more effective 27 pharmacological treatments. Whereas the medications that are widely used to treat PTSD were developed for 28 use in other disorders and are prescribed for long-term use, medication strategies that specifically target PTSD 29 symptoms and/or pathophysiology may be more effective and possibly even curative. Therefore, we propose to  neuroendocrine profile in PTSD is a unique one, best characterized by increased levels of corticotrophin-36 releasing hormone (CRH) (Bremner et al., 1997;Baker et al., 1999) and enhanced sensitivity to exogenous glucocorticoids in some, but not all, target tissue in the absence of hypercortisolism. Indeed, despite the 38 activation of CRH pathways, 24 hour urinary and plasma cortisol levels are often found to be low in PTSD 39 (Kanter et al., 2001;Yehuda, 2002). Numerous studies in veterans and civilians have demonstrated enhanced One hypothesis is that the up-regulation of glucocorticoid receptors in PTSD and increased sensitivity 48 to dexamethasone are secondary adaptations attempting to normalize inadequate glucocorticoid signaling (Raison and Miller, 2003). Low cortisol has been described in the initial aftermath to trauma in some trauma survivors who go on to develop PTSD and is often observed in those with chronic PTSD (Yehuda 2002). An 51 inadequate cortisol response at the time of trauma or in its aftermath may lead to a failure to constrain stress regarding side effects associated with long-term pharmacotherapy are common. If the initial trials in PTSD are

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successful, subsequent studies could assess myriad potential clinical applications in PTSD including single or 127 intermittent dosing as monotherapy, as an adjunctive treatment to enhance or accelerate the effects of other 128 pharmacological treatments or psychotherapy, and for PTSD prophylaxis following traumatic stress.

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The CCTA mechanism is being pursued since the ultimate goal is to develop a pharmacological 130 treatment strategy that is efficacious in veterans with PTSD. The use of this mechanism will ensure that 131 adequate clinical, scientific, and pharmaceutical oversight and resources will be available to pursue this goal;

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Phase II trials fall within the purview of the CCTA mechanism.

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In this initial trial we propose to study the effects of mifepristone in veterans with PTSD in order to 134 better detect a signal if there is one. Consistent with previous studies in neuropsychiatric disorders (Belanoff et  ), participants will be treated daily for one week with a high dose of mifepristone (600 mg/day) or 137 placebo and clinical outcomes will be determined at one month. The primary outcome will be the clinical 138 responder rate, with responders defined as a 30% reduction in the total PTSD symptom severity score (past 139 week symptom status) from baseline to four weeks derived from the Clinician Administered PTSD Scale 140 (CAPS). This definition of responder status has been used consistently in PTSD clinical trials. The response will 141 be based on the change in CAPS (past week symptom status) score from baseline to four weeks. To evaluate the 142 durability of the effects of this short-term treatment, participants will be assessed for up to three months.

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The impact of mifepristone on other clinical parameters will be described, including the three PTSD and its active metabolites inhibit the efflux of cortisol via the glycogen pump at the blood-brain barrier which 202 facilitates the uptake of cortisol into the brain (Sarkar, 2002); brain levels are further increased due to the 203 increased peripheral levels.

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Mineralocorticoid receptors (MR), which are activated at lower doses of cortisol, help to maintain 205 neuronal homeostasis and limit the disturbance caused by acute stress whereas GRs, which are occupied at 206 higher levels of cortisol, help to facilitate recovery from a stressor. The balance of MR/GR-mediated actions is 207 critical to homeostatic processes in the brain, and an imbalance leads to HPA axis dysregulation and associated 208 aberrations in metabolism, immune function, and memory function (De Kloet and Derijk, 2004). The Page 5 CCTA#0004 Protocol V2.1.1 (4/14/2015) Study Chair: Julia Golier, MD hormonal set points (Belanoff et al., 2002;Buckley et al., 2008) which could reverse some of the stress-related 211 neurobiological and allostatic changes that are associated with this disorder. Since the HPA axis in PTSD 212 appears to be dysregulated in a unique way, the full range of effects of GR antagonism in PTSD cannot be fully 213 predicted based on animal studies or studies in major depression. A systematic, empiric approach is needed to 214 examine the potential range of therapeutic effects in PTSD and their neuroendocrine correlates.

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Mifepristone has been studied in psychotic major depression (PMD). PMD and PTSD are both 216 characterized by elevated levels of CRH but many of the other neuroendocrine alterations are in opposite 217 directions in these two disorders. Thus, efficacy or lack of it would not predict efficacy in the other disorder.

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The clinical trial data are summarized to highlight the existence of evidence for the central effects of 219 mifepristone and recalibration of the HPA axis as well as abundant safety data (see section 2.a.3.).

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The initial trials of mifepristone in PMD include: 1) a crossover trial in which mifepristone (600 mg/day 221 x 4 days) was associated with rapid improvement in depression (Belanoff et

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In a subsequent Phase III trial of one week of mifepristone (600 mg/day), there was a site-by-treatment 229 interaction (Blasey et al., 2009). In the initial 20 study sites involved from the trial outset, there was a 230 significantly greater proportion of responders at day 56 in the mifepristone than the placebo group (26% vs.

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13%). In contrast, in the 9 additional sites added to boost enrollment, there was a higher placebo response rate.

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An analysis of trough mifepristone levels, which was specified a priori, showed that the response rates were 233 significantly higher in patients whose plasma mifepristone levels were at or above the pre-specified threshold 318 Deficient activity of the medial PFC in response to aversive stimuli (Shin et al., 2005) has been observed 319 in PTSD, and symptom improvement is associated with increased medial PFC activity (Seedat et al., 2004).

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PTSD is also associated with deficits in working memory (Vasterling et al., 1998;Stein et al., 2002), a memory 321 process mediated in part by the PFC. In healthy adults, working memory is very sensitive to the effects of 322 glucocorticoids (Lupien et al., 1999;Young et al., 1999), and working memory in PTSD participants is more

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Nonetheless, since mifepristone is contraindicated in adrenal insufficiency, for safety reasons participants with 364 a known history of this disorder or with low screening plasma cortisol levels will be excluded.

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The other portion was incubated with the same concentrations of DEX and 10μM of RU486 (mifepristone). At 423 baseline, the concentration of DEX at which lysozyme activity was inhibited by 50% (i.e., the lysozyme IC 50-DEX ) 424 was significantly lower in trauma exposed participants with PTSD compared to those without PTSD, indicative 425 of increased peripheral GR sensitivity (4.5 ±1.5 nM vs. 6.1 ±0.9 nM; F 1,15 =6.9, p=0.019). Co-incubation of cells 426 with mifepristone and DEX robustly antagonized the glucocorticoid response as shown in Figure 2.

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Mifepristone significantly shifted the IC 50 in response to DEX antagonized glucocorticoid responsivity on a 428 measure that is altered at baseline in PTSD, providing evidence that this medication targets a peripheral 429 biological characteristic associated with PTSD.

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In order to gain familiarity with mifepristone, we obtained pilot funding from the VISN 3 MIRECC to 431 study a small number of veterans with PTSD using similar inclusion/exclusion criteria to those that are 432 outlined in this protocol. Eight combat veterans with military-related PTSD were treated in a randomized, 433 double-blind trial of mifepristone (600 mg/day) or placebo for seven days and followed longitudinally for one 434 month. The data for each clinical and neuroendocrine outcome measure are shown in Table 1

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The acute decrease in GR number also points to the possibility increased cortisol binding and signaling.

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Moreover, this pilot clinical trial had a high retention rate and no adverse events or complaints about study 448 procedures were reported, suggesting that mifepristone treatment is safe, tolerable, and acceptable to veterans 449 with PTSD. Thus, these striking pilot data suggest that treatment with mifepristone is a feasible strategy that 450 may be effective in improving clinical outcomes in veterans with PTSD.

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Eligibility will be based on the inclusion and exclusion criteria which are enumerated below and in the Human

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Participants section. The inclusion and exclusion criteria were selected in order to include as representative a 465 sample as possible while also addressing safety concerns. Veterans who are actively suicidal as assessed by the 466 Columbia-Suicide Severity Rating Scale (C-SSRS) or who have attempted suicide within the past two years will 467 be excluded. (If suicidality is identified, the necessary steps will be taken to ensure the appropriate clinical care 468 is provided, and the local suicide prevention policies implemented.) Veterans with adrenal insufficiency will be 469 excluded, as will veterans with other major medical or neurological illnesses, as they may be at increased risk of 470 developing adverse events. Veterans with renal disease/impairment, hepatic disease/impairment, cardiac 471 illness (e.g. coronary vascular disease, congestive heart failure), or hypokalemia at screening will also be 472 excluded. Since mifepristone use can prolong the QTc interval in a dose-related manner, veterans with a 473 prolonged QTc interval, defined as >450 msec, on the ECG at screening will be excluded. To evaluate QTc 474 prolongation post-mifepristone treatment, an ECG will also be performed at both the 3 day follow up visit (visit 475 1.5) and 1 week follow-up visit (week 1, visit 2).

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Participants on potent CYP3A4 inhibitors (fluconazole, ketoconazole, itraconazole, erythromycin, 477 rifampin) and some anticonvulsants (e.g., phenytoin, phenobarbital, and carbamazepine) will be excluded 478 since these medications impact the metabolism of mifepristone (see Risk/Benefit Assessment for details). Due

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to an increased risk of adverse drug reactions, veterans taking simvastatin, lovastatin, fentanyl, pimozide, 480 bupropion, nefazodone, dihydroergotamine, ergotamine, quinidine, sirolimus, carvedilol, propanolol, 481 diltiazem, verapamil, alprazolam, or tacrolimus will also be excluded. Since the impact of mifepristone on the 482 male reproductive system has not been extensively studied, only veterans willing to use effective means of birth 483 control for up to 90 days after mifepristone ingestion will be eligible; this will cover the critical period of fetal 484 development.

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Additionally, veterans diagnosed with alcohol/substance abuse and dependence will be excluded only if 502 they are recently engaged in a maladaptive pattern of use or abuse. More specifically, persons who meet 503 diagnostic criteria for alcohol/substance dependence will be excluded if they have manifested dependence 504 within the previous three months (i.e., have met three or more of the seven criteria for a maladaptive pattern of 505 use in the last three months). Persons with alcohol/substance abuse (who, by definition, do not meet criteria 506 for alcohol dependence) will be excluded if they have shown a maladaptive pattern of alcohol use during the 507 past one month (i.e., have met one or more of the four criteria for a maladaptive pattern of abuse).

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Veterans who are currently receiving psychotherapies -individually or in a group setting -that are 509 considered to have significant benefit for PTSD, according to the VA and DoD's Treatment Guidelines, will also 510 be excluded. These therapies are cognitive therapy for PTSD (e.g. cognitive processing therapy (CPT)), 511 exposure therapy (e.g., prolonged exposure therapy), stress inoculation training, and eye movement 512 desensitization and reprocessing (EMDR). Other forms of therapy and case management which do not 513 specifically target PTSD symptoms and/or have not been shown to provide significant benefit in PTSD will be 514 allowed at entry and throughout the study (e.g. supportive therapy, psychodynamic therapy, anger 515 management, cognitive behavioral therapy for symptoms or problems other than PTSD).

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We recognize that PTSD in women is increasingly common and effective treatments are needed for this 517 group as well. However, women will be excluded from this initial trial for safety reasons, since mifepristone is 518 an abortifacient. Should mifepristone prove to be effective in male veterans with PTSD, this would provide a 519 rationale for future studies in women, employing additional safeguards. 572 approval for a partial HIPAA waiver, by direct contacts after chart reviews and physician consultations for 573 patients with PTSD. Before contacting potentially eligible patients, the study team will review the clinical 574 history in the electronic patient chart at the site to investigate inclusion and exclusion criteria. For those 575 eligibility items not found in the chart or found but out-of-date, the study team will determine what 576 information needs to be obtained during the pre-consent and post-consent screening visits. Once it is mutually 577 agreed upon that the patient is eligible for trial participation, that the strategy within the protocol is clinically 578 acceptable, and that the primary physician is agreeable to the patient being contacted for possible study 579 participation, patients will be contacted. The method for this contact, (i.e. by phone or letter and with pre-580 established oral or written scripts) will require approval by the governing IRB. If patients from any of the above 581 contact sources agree to be evaluated, they will have an initial visit with the study team. During this visit, the 582 study team will ensure the patient fits the study's inclusion criteria and does not have a reason to be 583 excluded. The study will be explained to them and the Informed Consent Form (ICF) will be reviewed in its 584 entirety. At that time, or after further consideration of the study by the patient and his physician and family, 585 the patient will be asked to sign the ICF and HIPAA authorization, copies of which will be given to them. The 586 investigators consider this consent process to be an ongoing process maintained throughout the study to 587 provide patients with a continued understanding of the protocol, their participation, and their rights as human 588 research participants. Remuneration is provided for time and expenses ($25 for screening/medical evaluation; 589 $50 per visit for a total of four visits (baseline, one week follow-up, one month follow-up, three month follow-590 up)), but is not so high as to coerce an individual to participate who would not otherwise participate (see

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Human Subjects section for more information on participant remuneration). After the signed ICF is obtained, 592 additional screening procedures covered in the ICF will be conducted prior to randomization.

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Participant recruitment will be the responsibility of the clinical research staff and local principal 594 investigator (PI). The study staff will educate their clinical colleagues regarding this study opportunity.

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Veterans with a confirmed or presumptive diagnosis of PTSD will be identified in VA outpatient clinics (e.g.

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PTSD, mental health, or primary care clinics). Mental health professionals at the VA will be alerted about the 597 study and the study staff will maintain frequent communication with them so that potentially eligible veterans 598 will be referred to the study. Veterans expressing an interest in learning more will be referred to study 599 personnel for preliminary screening and informed consent. Informed consent will be obtained by the study PI 600 or by an IRB-approved delegate after a screening interview, but prior to the initiation of any study procedures.

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As the initial step in the consent process, the study will be explained to the veteran in detail and the consent Page 13 CCTA#0004 Protocol V2.1.1 (4/14/2015) Study Chair: Julia Golier, MD form will be read to the veteran in its entirety by the PI or an IRB-approved delegate. The participant will be 603 fully informed about all aspects of this study and will be given ample time for clarification and to have his 604 questions answered. The veteran will be able to bring the consent form home and can discuss the study with his 605 physician, family members, or others prior to making a decision. A de-identified log will be kept of all veterans 606 who are screened for the study, even if they are ineligible, in order to characterize the larger population from 607 which the sample was drawn and the reasons veterans were found to be ineligible.

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Blood samples will be obtained for the assessment of basal pre-treatment neuroendocrine activity (i.e., 627 plasma cortisol and ACTH levels). Veterans will be called the day before their scheduled visit and asked to fast 628 from midnight until after the blood draw.10 ml of blood will be drawn by routine venipuncture for the

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To address quantity and frequency of alcohol use within the last 30 days, participants will be asked to 640 answer three NIAAA questions. This information will be obtained at baseline, 1 week follow-up, 1 month 641 follow-up, and 3 month follow-up. Participants will be asked to report how many days per week or days per 642 month they had at least one alcoholic beverage (defined as 1 can or bottle of beer, 1 glass of wine, 1 can or bottle 643 of wine cooler, 1 cocktail, or 1 shot of liquor) in the last 30 days, how many drinks they consumed on average on 644 the days in which they drank, and how many times during the last 30 days they consumed 5 or more drinks on 645 one occasion. This measure will be used as a potential covariate to examine the effects of alcohol use on clinical 646 outcomes.

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Since grapefruit juice may increase the amount of mifepristone in blood and increase the chance of 648 adverse events, participants will be instructed to not drink grapefruit juice while they are taking study 649 medication.
Participants will be randomized at the end of the baseline visit, and will receive study medication.

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Patients determined to be eligible and willing to participate in the study will be randomly assigned to 666 600 mg mifepristone or placebo using a web-based randomization system with a telephone call randomization 667 system as back-up. The clinical research assistant at the participating facility will be required to sign into this 668 password-protected site. The clinical research assistant will enter the patient study number and will be asked to 669 answer a few questions about eligibility in order to complete the randomization procedure. If met, the website 670 will select the first unused entry from the pre-specified list of random treatment assignments for the particular 671 site and then assign a randomization number, which will be used to order the double-blind treatment 672 prescription from the study site pharmacy. The randomization lists are stored on a secure server at Hines CSP 673 Central Study File labeled "restricted access". A copy of appropriately executed and completed consent and 674 HIPAA authorization documents must be on file at the Hines CSPCC within 24 hours of randomization,

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preferably before the patient is randomized. If the internet server is down during normal business hours, the 676 clinical research assistant can telephone the Hines CSPCC to randomize a patient.

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Medication treatment will be for one week duration, and randomized participants will be given a seven-686 day supply of medication. Three weeks after the pulse treatment, the participant will undergo clinical 687 reassessment. If participants develop an AE or as SAE that is deemed unsafe by the PI, they will be taken off 688 treatment immediately but will be followed per protocol. The research team does not anticipate the occurrence 689 of study-related SAEs, as the dose levels used in this trial have been used before in other studies without SAEs.

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In our pilot study of mifepristone in PTSD, no veterans were taken off treatment.

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Both the active study medication and its matching placebo will be donated by Corcept Therapeutics.

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The study physician will assume the psychiatric care of the participant for the duration of the study. A

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As outlined in Table 2, the veteran will be assessed in person 48 to 72 hours after taking the first dose of 701 the study drug. An ECG, vital signs (pulse, blood pressure, temperature), and medical labs (complete blood cell 702 count, fasting glucose, cortisol, and electrolytes) will be taken. Any symptoms and changes in concomitant 703 medications will also be reviewed. The checkup is intended for safety reasons. Follow ups will occur 704 immediately after the pulsed treatment (one week follow-up), at one month follow-up, and at three month concomitant medication use. In addition, blood will be drawn for medical labs (complete blood cell count, 708 fasting glucose, and electrolytes) and neuroendocrine assessment (plasma cortisol and ACTH) at the day 3, one 709 week and one month follow-up visits; an ECG will also be performed at the one week follow-up visit. Refer to 710 figure 3 for a timeline of study visits.

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In order to quantify the amount of co-therapy the participant receives during the study, the 712 psychosocial treatment schedule provided in the Longitudinal Interval Follow-up Evaluation (LIFE) study will 713 be used. With this instrument we will collect data about the types of therapy the veteran has received.

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Specifically, we will collect information about the number of sessions per week that the patient has had of the 715 following types of therapy: individual, group, family, medication session, or self-help. The information will be 716 collected at one month intervals (1 month follow-up (week 4, visit 4); 2 month follow-up telephone check-in 717 (week 8, visit 6); 3 month follow-up (week 12, visit 8).

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Additionally, the clinical research assistant will be responsible for contacting the study participant in-719 between visits via telephone (i.e., week 2 (visit 3), week 6 (visit 5), week 8 (visit 6), and visit 10 (visit 7)) so that 720 contact will be made with the participant at least every two weeks.

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All participants who exit the study prematurely during the acute treatment period will be encouraged to 795 come in for a final termination visit for the assessment of adverse events, vital signs, and medical laboratory 796 testing. All unused medication will be collected and sent to the study site pharmacy. The veteran will also be 797 asked to complete a final clinical assessment three weeks after their last dose of medication. If any medical 798 complication has arisen, an appropriate medical referral will be made. At study endpoint, the patient will be 799 informed that the active study period has ended and that they will resume routine clinical care. To facilitate the 800 transition, the veteran's psychiatrist or other mental health care provider will be informed about study 801 completion and of any clinically important developments that occurred during the study. The site PI will ensure 802 that the veteran has an adequate supply of medication until that visit and will provide care as needed until 803 routine care is re-established. The veteran will be informed at the outset of the study that continuation on 804 mifepristone will not be available to them after the study period ends. To preserve the integrity of the study, we 805 will wait until follow-up on all patients is complete and then break the randomization code on all patients. A 806 communication will then be sent to the patient informing them if they were on active treatment or placebo.

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Steps taken to minimize risk include excluding veterans with major medical illnesses including adrenal 810 insufficiency, diabetes mellitus, and a history of severe TBI. The initial health assessment will consist of a 811 medical history and physical examination with measurement of vital signs, weight, height, and laboratory 812 testing (complete blood cell count, fasting glucose, electrolytes, magnesium, morning cortisol, creatinine, 813 thyroid stimulating hormone, liver function tests, lipid profile, urinalysis, and ECG). For clinical safety 814 monitoring during the trial, complete blood cell count, fasting glucose, electrolytes, and vital signs will be 815 measured during the 3 day follow-up and one week follow-up visits. At day 3, blood will also be collected for 816 cortisol and stored frozen for subsequent analysis at the Core Lab, located at the James J. Peter's VA Medical

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Center. The day 3 cortisol sample will be analyzed in the same manner as the day 7 sample, in batches, after the 818 participant completes all study procedures. In the event of a significant AE or SAE, a blood sample will be

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events known to be associated with mifepristone will be assessed using the reference toxicity table included in 828 the study manual of operations to decrease the variability across investigative sites. Per the FDA's request, the 829 investigators will explicitly inquire about the development of a rash since this is a known side effect of 830 mifepristone. Medication will be discontinued if a rash develops or adrenal insufficiency is suspected; for the 831 latter, a referral to internal medicine and/or endocrinology will be made. If the rash is severe or persistent, the 832 veteran should be referred to a dermatologist.

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With respect to suicidality, veterans with a history of attempted suicide within the previous two years or 834 active suicidal ideation within the past month (participant endorses active suicidal ideation with any methods 835 without intention to act (question 3)), as assessed by the C-SSRS, will be excluded. For all study participants, 836 suicidality will be re-assessed at in-person post-treatment visits (one week follow-up, one month follow-up, 837 and three month follow-up) using the C-SSRS. If the participant develops active suicidal ideation (as elicited 838 from the C-SSRS or spontaneously reported) at any point in the study, he will be further assessed; the 839 appropriate clinical intervention will be initiated and the local procedures for notifying the suicide prevention 840 coordinator will be followed.

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To assist in monitoring patient safety, the sites will be provided with an Investigational Brochure (IB) 852 Study participants will be monitored at each clinic visit (day 3, weeks 1, 4, and 12) and via telephone 853 contact (weeks 2, 6, 8, and 10) by site investigators and coordinators for AEs and SAEs. Participants will be 854 asked about any AEs or SAEs that have occurred since the previous visit or telephone contact, and vital signs 855 will be obtained at all in-person visits. This frequent contact with participants, both in-person and via 856 telephone, will enable site investigators to monitor safety, obtain PTSD symptom ratings, and identify any 857 signs of deterioration. Information on all AEs and SAEs, including those related to the study intervention and 858 those not related to the intervention, will be collected and recorded on the appropriate study event forms. All 859 relevant information (e.g. onset of event, severity, outcome, extent to which it is or is not attributable to the 860 drug or other study procedures) will be captured. Active monitoring of AEs and SAEs will begin as soon as a 861 study participant signs the informed consent document and will continue through end-of-study for each 862 participant. Instructions for contacting the VA National Suicide Hotline will be incorporated into the consent 863 form and instructions for patients as part of safety monitoring. These safety data will be analyzed as described 864 in the Analysis Plan (4.q.) and used to inform additional studies with mifepristone in the treatment of PTSD.

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The primary clinical outcome measure will be clinical response status at study endpoint (week 4), 908 defined as a 30% or greater reduction in CAPS total score from baseline to week 4. Response status at week 12 909 will also be assessed as a secondary outcome measure. Total symptom severity during the prior week will be 910 measured using the CAPS (Blake et al., 1995), a well-validated scale widely used in outcome studies of PTSD.

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PTSD symptom severity is calculated by summing the frequency and intensity rating of each of the 17 PTSD 912 symptom items.

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The secondary outcome measures will be the change in CAPS score from baseline to 1 week, 4 weeks 914 and 12 weeks, the presence of clinical response as defined above at 12 weeks, and the percentage of study drug 915 related AEs or SAEs.

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The descriptive clinical outcome measures will be change from baseline to week 4 and week 12 for the

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Neuroendocrine outcomes include change from baseline to post-pulse treatment in plasma cortisol and 923 ACTH levels. These will allow for assessment of the acute neuroendocrine response to 600 mg of mifepristone 924 and its relationship to treatment outcome. Additionally, plasma levels of mifepristone and its metabolites will 925 be assessed immediately after one week of treatment.

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Prior to study initiation, the protocol and recruitment/consent materials will need to be reviewed for 948 approval by the local site VA-IRBs. These bodies will provide a review for multi-center trials within the CSR&D,

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HSR&D, and RR&D branches of ORD. The local site VA-IRBs will also receive and review amendments, SAEs, 950 and protocol deviations, and will perform annual continuing review certification. Finally, the study protocol 951 and progress must be reviewed by the individual study site R&D Committees before site initiation, and 952 annually thereafter.

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Training will be provided before and at the kick off meeting for the CAPS and SCID, and the scoring 954 conventions for this study will be reviewed in detail. Following the training session, all evaluators will send an 955 audio-tape of their first two CAPS interviews for review by Dr. Janine Flory, the lead psychologist for this 956 study, or a designated alternate. Feedback will be provided to the evaluators regarding their adherence to the 957 structured format of the interviews and the use of follow up or clarification questions. The nature of this 958 feedback will be qualitative.

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Audio recordings of at least three CAPS interviews of male patients with PTSD will be sent to the sites 960 for assessment of inter-rater agreement. The site interviewer's ratings and the study chair psychologist's ratings 961 for total symptom severity (current) will be compared and an intra-class coefficient (ICC) will be determined.

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An ICC greater than or equal to 70% will be required. After reliability has been established, a random sample of 963 10% of the CAPS performed at each site will be selected and scored by each of the site interviewers for ongoing 964 assessment of fidelity and reliability. Thus, each site will provide approximately 1 recording annually for 965 ongoing inter-rater reliability.

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An Olympus WS-802 personal digital recorder will be utilized by each assessor to record CAPS 967 interviews. The WS-802 contains an external memory slot which enables users to copy audio files onto a 968 microSD card. When not in use, all WS-802 digital recorders will be stored securely behind a locked door.

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Audio recordings that are selected for review will be transferred from the recorder to a microSD card (directly) 970 and mailed to the Bronx VA via a traceable mail system (i.e., UPS) or courier service. These recordings will not 971 contain PHI and files stored on the card will not be indexed by any identifiable means. Once received, the files 972 will be transferred onto an IRM-approved, non-VA computer, and deleted from the card. They will then be 973 uploaded to the VA-approved secure SharePoint server which will only be accessible by few designated study 974 assessor personnel via a privacy setting. The SharePoint site can only be accessed using VA-secured computers.

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Once the audio has been listened to and scored, it will be deleted from the computer. The microSD card that 976 contained the audio file will be formatted and sent back to the site in which it originated from.

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Participants who agree to be recorded will sign VA consent form 10-3203. Those who decline to be 978 audiotaped will not be excluded from the study. A telephone conference call will be held every one to two 979 months, depending on volume, with the site interviewers and Dr. Flory to discuss CAPS scoring, consensus 980 diagnoses, and to review difficult clinical cases. The study DMC will be the CSR&D Psychiatric, Behavioral Health & Neurologic Disorders Central Data

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Monitoring Committee. The cDMC will initially meet before or at study start-up, determining at the first 983 meeting the frequency of progress reviews required for the study, but will meet no less than annually. The 984 cDMC will review the progress of the study including patient intake, completeness of follow-up, data quality, 985 protocol deviations, and safety, and will also review any protocol modifications recommended by the EC. The 986 cDMC will intermittently review data provided by study statisticians. The cDMC will make recommendations to 987 the Director, CSR&D, through the Director, Hines CSPCC, as to whether the study should continue, be placed 988 on probation, or be terminated.

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The Study Group, which consists of all participating investigators and site clinical research assistants 990 and assistants, will meet annually to discuss the progress of the study and any problems encountered during 991 the conduct of the trial. Study personnel will adhere to ORD policy on human subjects' protections by fully

000
Toward the end of the start-up period, training of study personnel will take place during a kick-off 001 meeting. All participating investigators, site clinical research assistants, and CSP coordinating center personnel 002 will attend. Prior to the meeting, case report forms will be finalized and a detailed manual of study operations 003 will be written and circulated. This manual will serve as the training manual for the meeting and as a reference 004 document following the meeting. The study Chair's office (consisting of Dr. Golier, a research psychologist, and 005 clinical research assistant) and the data and pharmacy coordinating centers will provide the training. The 006 general training will include the study treatment, patient screening and consent, baseline evaluation, follow-up 007 procedures, proper entry and maintenance of data, and AE/SAE safety reporting. In a special training session 008 (see below), study clinical research assistants from all participating sites will be trained in the administration of 009 a variety of state-of-the-art assessment instruments by the research psychologist to ensure accuracy and 010 precision of administration of the instruments and to maximize inter-rater reliability. Training on the CAPS 011 and SCID will be performed at the initial kick-off. A formal training on the CAPS and SCID will be provided at 012 the kick-off meeting by the research psychologist who is an expert rater and who will establish inter-rater 013 reliability. Inter-rater reliability coefficients of greater than 0.70 will be established for the total CAPS score.

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Quarterly supervision on the CAPS administration will be provided to ensure continued integrity of these 015 assessments and inter-rater reliability will be re-assessed annually. Replacement staff will be trained as 016 needed.
017 018 4.l.3. Site Performance 019 Hines CSPCC will evaluate recruitment and retention performance monthly. Other performance 020 problems such as protocol deviations, poor data quality, missing or overdue data, and reasons for withdrawal 021 from the study will also be tracked. A monthly study conference call for study personnel including Hines 022 CSPCC, PCC, Chair's office, and all sites will be held to review study performance. Study sites will be put on  The Hines CSPCC will manage the trial data using a web-based eDC system. Paper source documents 031 will be provided to clinical research assistants as a primary means of collecting data. After a patient consents to 032 participate in the study, the site clinical research assistant will create a patient casebook, which will contain the 033 consent forms, all relevant source documents, and any other information pertinent to the study. The case Page 22 CCTA#0004 Protocol V2.1.1 (4/14/2015) Study Chair: Julia Golier, MD report forms will be completed at each visit through the Cooperative Studies Program's password-protected 035 eDC system, accessed via the VA intranet. The eDC system will allow clinical research assistants to enter the 036 source document data directly into a web-based study database and thus manage their patient's study activity, 037 handle data clarifications, and correct patient data online. Accordingly, the electronic system will be used to 038 create, modify, maintain, and retrieve clinical data for CCTA #0004 during each step of data collection

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After the study is approved, the Study Chairman, Study Biostatistician, Study Project Manager and 043 Study Pharmacist will prepare an Operations Manual for site staff to guide them through the operation and 044 management of the study and data collection tools. A training session will occur at the study kick-off meeting 045 for all investigators and clinical research assistants to assure uniformity in patient management, data 046 collection, study procedures, and Good Clinical Practices. At this training, clinical research assistants will be 047 provided with reference materials on the software tools and tasks. Once formal training is completed, user 048 accounts -utilizing a URL specific to the study to access and use the system and enter patient data -will be 049 activated. Accounts will be password protected and unique to the users' functional study group (i.e., those for a 050 clinical research assistant would differ from those of the coordinating center or site monitors). Formal training 051 on the use of the eDC system for clinical study management will also be provided. Systems training will also be 052 held at annual meetings and on an as-needed basis for new study personnel. The study personnel, including the 053 biostatistician, statistical programmer, database programmer, and data coordinator at Hines CSPCC, will have 054 access to read the data.

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CSP has developed an eDC tool that is fully compliant with US Federal regulations regarding electronic 056 web-based data capture systems established by the Food and Drug Administration under 21 CFR 11. This 057 system is designed to make the process of patient data management easier, timelier, and more efficient. It is 058 accessed via the VA intranet. The paper source documents from which data will be entered into the electronic 059 data capture tool's case report forms provide the official clinical record for data collection. All paper-based 060 study records will be kept under lock and key. The eDC system will be validated by the Hines CSPCC Validation

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Team to ensure the integrity of the data capture software. Validation documentation and all system 062 dependability documentation (i.e., software and hardware versions, etc.) will be maintained as study 063 documentation, but have not been detailed in this protocol.

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For this trial, eDC designers will create a study-specific database that includes case report forms, 065 interview schedules, and data queries using customized C# code imbedded directly into Microsoft InfoPath 066 (2007 or later) forms housed on a VA approved SharePoint Server Farm (2007 MOSS or later). Data queries 067 will be managed in two ways. Certain queries will be programmed into the forms that are designed to activate 068 upon data entry. Additional queries will be programmed using other data analysis tools such as SAS and will be 069 uploaded into the system for clinical research assistants to address. Furthermore, the system will allow manual 070 queries to be entered into the forms by the coordinating center as needed. Updates to the electronic forms and 071 database can be generated during the study without impacting collected data. Study reports can be generated 072 from exported data in order to track the study progress and to monitor adverse events, in particular SAEs.

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Electronic data capture methods will be used for the proposed study. The data will be entered by site 078 clinical research assistants remotely through electronic case report forms. Extensive data checks, including 079 missing values, out-of range entries, and consistency between variables, both within and across forms, will be 080 built into the computerized data capture system developed for this project. There will be two levels of checking.

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The first level will be done at the time the data is entered into the case report form. These checks will 082 automatically appear on the screen at the time of entry. After submission of the form into the database, second-083 level checks against other data already captured for that patient will be done. These checks will generate data 084 discrepancies, which will be stored in the eDC system for the site clinical research assistant to access and 085 rectify. Any revisions to the data made by the study site personnel will be recorded in a system audit trail. The

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Hines CSPCC. Contact form information will be entered into the electronic system as password-protected files.

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Two mirror-images of the study database will be housed on separate servers located at different secure 107 VA facilities that support round-the-clock web services and monitoring within a secure VA environment in 108 order to provide an optimal infrastructure for the protection of sensitive information. Data entered by the site 109 clinical research assistant is sent to the production server which is then copied, almost continuously to a back-110 up server at a different location. The clinical database with all research data will be housed behind the VA 111 firewall on VA owned and maintained servers. Accordingly, the information housed within the eDC system will 112 be afforded the same level of security as all forms of VA protected and/or highly sensitive information.
113 Additionally, the system will be monitored by the Hines CSPCC Quality Assurance and Information Technology 114 teams to ensure that all applicable VA regulations and directives are strictly followed.

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Backup copies of the database will be transferred behind the VA firewall to the Hines CSPCC on a 116 frequent basis depending on the study need (at least once per day). These backup copies will be transferred and 117 stored across secure connections according to VA regulations and Hines CSPCC operating procedures. Periodic 118 off-site back-ups will be made as part of a comprehensive disaster recovery plan. The Director of Information 119 Technology will ensure that backup media are stored in compliance with all federal and VA regulations on the 120 storage of potentially sensitive information. The Director of Information Technology will also ensure that all 121 backup media is encrypted in compliance with the current best practices established and approved by the 122 Center Director(s). Encrypted backup media will be stored in a physically secure location with access restricted 123 to essential personnel. Access to back-ups may be at the discretion of the Center Director(s) and/or the

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At the CSPCRPCC, the following four staff positions will have access to PHI. Individuals in these 145 positions will be able to access de-identified forms of PHI: A. Clinical Monitors, B. Study Pharmacist, C.

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Adverse Event Specialist (Regulatory Affairs and Safety Officer) and D. Pharmacy Project Manager

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Research data will only be stored on secure VA servers within the VA firewall. Data will not be stored on 148 desktops or on University affiliate servers. Study data will be coded with a unique study identifier for each 149 participant and stored in a de-identified manner. Identifiable information will be collected for patient tracking 150 and safety purposes. All private information will be kept on an encrypted, password-protected server to which a 151 small number of people will have access. Access to the cross-walk file linking the participant's identifiers and 152 their study data will be restricted to the clinical site and to the approved personnel at the coordinating center.
153 This file will be destroyed according to CSP policy.

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While the study is on-going, the electronic data capture systems will utilize state-of-the-art technologies 155 in order to protect the data during transmission. All of these technologies exceed the current VA standards for 156 transport. In brief, electronic systems will employ secure socket layer technology and FIPS 140-2 compliant 157 encryption algorithms to ensure that data is not vulnerable during transport. In addition, all data will be stored 158 within the VA firewall and will be password protected at all times. Hard copy data will be sent via a traceable 159 mail system (i.e., UPS), via a courier, or via secure fax. Faxes are electronically routed to document 160 management systems housed on VA protected servers located at the Regional Data Center in Philadelphia, PA.

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Access to these secure fax servers is restricted to the coordinating center personnel with approved access to the

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In order to ensure on-going reliability and fidelity of CAPS assessment, the study-specific SharePoint 170 site will be used to securely share 10% of randomly selected CAPS audio recordings. Recordings selected for 171 review will be transferred from the audio recorder to a microSD card (directly) by study personnel at each site 172 and mailed to the Bronx VA via a traceable mail system (i.e., UPS) or courier service. These recordings will not 173 contain PHI and files stored on the card will not be indexed by any identifiable means. Once received, the files 174 will be transferred onto an IRM-approved, non-VA computer, and deleted from the card. They will then be 175 uploaded to the VA-approved secure SharePoint server which will only be accessible by few designated study 176 assessor personnel via a privacy setting. The SharePoint site can only be accessed using VA-secured computers 177 and is regulated by the SharePoint administrators at the Hines VA. Once the audio has been listened to and 178 scored, it will be deleted from each user's workstation. The microSD card that contained the audio file will be 179 formatted and sent back to the site in which it originated from via a traceable mail system (i.e., UPS) or courier 180 service.

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The clinical data for CCTA #0004 are considered property of the Cooperative Studies Program and shall 182 not be sent off-site (i.e., outside of the Hines CSPCC) without the expressed, written permission from the Hines 183 CSPCC Center Director and CSP Central Office. All data transfer and data security policies of the Cooperative 184 Studies Program will be closely followed.

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Retention and destruction of data will be conducted according to CSP operating procedures, as well as 186 federal and local VA regulations. This will include paper and electronic data stored at the local sites, the Hines

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The main aim of this study is to evaluate the potential efficacy of 600 mg mifepristone vs. placebo using 199 a signal detection approach commonly used in Phase IIa drug-development trials. The approach was first 200 specified by Simon et al. (1985) and falls within the class of ranking and selection procedures (Gibbons, Olkin

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and Sobel (1977)). Specifically, a response rate difference that is considered clinically relevant is selected (15% 202 in this study). The sample size is based on providing a pre-specified degree of certainty (90% in this study) that 203 if the response rate difference is observed, the treatment group with the higher response rate has been correctly 204 identified. The analysis of the primary outcome then becomes a binary decision rule (i.e. has the pre-specified 205 response rate difference been observed (yes or no)). The mifepristone 600 mg/day will be compared to placebo 206 over a short duration, as is commonly done in Phase IIa trials. The advantage of using such design for this 207 study is to detect the signal for comparing the 600 mg group vs. placebo while keeping the sample size small.

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The results generated from this study will provide the basis for a larger, more definitive, Phase III trial when

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This study will use a 30% reduction in CAPS total score from baseline to four week follow-up to classify 226 the participants as responders vs. non-responders. The proportion of responders to 600 mg mifepristone will 227 be compared to the proportion of responders to placebo. The referenced studies report response rate 228 differences ranging from 16% to 30% and placebo response rates ranging from 20% to 44%. In the present 229 study, we will consider a 15% difference in the proportion of treatment vs. control group responders to be

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Active recruitment will take place over 31 months. To assess the feasibility of recruiting the proposed number 251 of participants the VHA Support Services Center data files for Special Focus Groups were reviewed to 252 determine how many combat veterans with PTSD currently seek care at each of the potential sites.

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Questionnaires were sent to the sites listed in Table 3

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Montrose, East Orange) and community-based outpatient clinics.

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The team at Durham has a vast amount of experience with randomized controlled medication studies in 275 PTSD and is well versed in performing the assessments and evaluations that will be used in the present study.    Exploratory Analysis of Primary Outcome -The primary outcome will also be explored for subgroups as defined 350 by concurrent psychotropic medication use status and classification prior to randomization. The mITT 351 principle will also be applied in the secondary and exploratory analyses of the primary outcome.

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Sensitivity Analysis of Missing Data-In the analyses mentioned above, missing data will be replaced using 354 three additional procedures. The first procedure will entail the assumption of "worst case scenario" where the 355 participants with missing data at week 4 will be deemed non-responders. This approach will provide a 356 conservative test of treatment effects. In the second procedure, the last available information about the 357 primary outcome, if available at week 1, will be used to impute the missing data at week 4 and if missing at both 358 week 1 and 4, participants will be deemed non-responders. The third procedure involves the comparison on all 359 participants whose CAPS score are obtained on week 4.

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Secondary Outcomes: 362 363 1. The analysis specified for the one-month responder rate will also be done for the three-month 364 responder rate as a secondary analysis to check for the sustainability of the response.

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Additionally, a continuous mixed-effects model for longitudinal observations of CAPS (past week 367 symptom status) scores (week 1, 4 and 12) will be used. Covariates including baseline characteristics, 368 specifically duration of symptoms, duration of illness since trauma, concurrent psychotropic medication 369 use prior to randomization, overall extent of the psychiatric co-morbidity, military cohort, and site will 370 be explored in the adjusted analysis. This analysis will provide a treatment effect in terms of the slope of 371 the interaction term between group and time variables, conditional on aforementioned covariates under 372 the missing at random (MAR) assumption (Laird and Ware, 1982).

374
The above mentioned analyses will be performed based on a mITT principle.

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2. To describe the safety and tolerability mifepristone, information on all related and unrelated SAEs will 377 be collected. There will be accelerated safety reporting for every two adverse events in every ten 378 participants. The specific AE(s) leading to the withdrawal of a patient from study participation will be 379 collected, along with characteristics of the AE including severity, duration, and whether the withdrawal 380 was at the request of the patient or was initiated by a study investigator or other clinician. The AE rate 381 will be determined on the basis of occurrence of at least one adverse event in each participant, and the 382 following comparisons will be carried out:

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The safety analysis will be performed based on safety population. All randomized patients who have 399 received at least one dose of study medication will be included in the safety analysis according to the 400 treatment groups to which they are randomized.

404
Descriptive statistics and confidence intervals for the change from baseline to one month follow-up 405 and to three month follow-up for each of the two treatment groups will be provided for each of the 406 descriptive outcome measures. Additionally, comparisons between mifepristone and placebo will be 407 performed; however, lack of statistical significance should not be construed as evidence of no clinical 408 effect given the small sample size. All efficacy analyses on descriptive outcomes will be performed 409 based on a mITT principle. 410 411 1. PTSD Symptom Sub-Scales 412 a. Descriptive statistics for the change in score from baseline to one month on the three PTSD 413 symptom sub-scales (intrusions, hyperarousal, and avoidance) and confidence intervals will be 414 provided for each treatment group.

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b. Change in score from baseline to one month on the three PTSD symptom sub-scales (intrusions, 416 hyperarousal, and avoidance) will be compared between mifepristone and placebo using two- associated with a body rash which resolved when the medication is discontinued. Mifepristone use has also 530 been associated with nausea, fatigue, headache, hot flashes, and breast tenderness in long-term trials in 531 medical diseases. There is a remote chance that mifepristone, by blocking the effects of the stress hormone 532 cortisol, could cause functional adrenal insufficiency; therefore, persons with adrenal insufficiency or with low 533 baseline cortisol levels will be excluded. Additionally, patients will be monitored for signs and symptoms of 534 adrenal insufficiency during the trial (severe fatigue, weakness, nausea, vomiting). Patients who have renal 535 disease/impairment, hepatic disease/impairment, hypokalemia, and prolonged QTc interval>450 msec on 536 ECG at screening will also be excluded. Patients taking simvastatin, lovastatin, fentanyl, pimozide, bupropion, 537 nefazodone, dihydroergotamine, ergotamine, quinidine, sirolimus, alprazolam, or tacrolimus have an increased 538 risk of adverse events associated with mifepristone use; therefore, participants who receive these drugs will 539 also be excluded. Since grapefruit juice may increase the amount of mifepristone in the blood and may increase 540 the chance of side effects, participants will be instructed to not drink grapefruit juice while they are taking 541 study medication. Other efforts have been made to further reduce the risks associated with mifepristone, such 542 as excluding patients with diabetes and other major medical illnesses, and monitoring of laboratory values, 543 vital signs, and clinical state during the trial. Based on mifepristone's extensive hepatic metabolism by CYP3A4, 544 it is possible that potent inhibitors of this enzyme (e.g., fluconazole, ketoconazole, itraconazole, and 545 erythromycin) could increase mifepristone's blood levels and decrease CYP3A4-mediated generation of its 546 active metabolites. Furthermore, rifampin and certain anticonvulsants (e.g., phenytoin, phenobarbital, and 547 carbamazepine) can considerably accelerate mifepristone's metabolism, decreasing the levels of both 548 mifepristone and its metabolites. Because such interactions have the potential to significantly impact safety 549 and response levels, patients who need to receive strong CYP3A4 inducers or inhibitors as maintenance 550 therapy will be excluded from the study. In addition, randomization will not take place until at least five of 551 these agents' half-lives have expired.

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Potential benefits: Since there are few effective treatments for PTSD in veterans, identification of an 554 effective treatment or of a biological target for treatment would be very beneficial; the medication has been 555 found to be safe and tolerable in other neuropsychiatric conditions; thus, the overall risk/benefit ratio is 556 favorable.